The present invention is directed to a pressure sensitive adhesive composition useful in transdermal administration of pharmacologically active agents.
The transdermal delivery of therapeutic agents has been the subject of intense research and development for over 20 years. These efforts have resulted in the creation of several commercially successful products whose advantages over other dosage forms are well documented.
The skin, however, is an exceptionally well designed barrier. As a result, only a relatively small number of drug molecules are suitable for transdermal delivery.
Various techniques have been explored in an attempt to enhance the permeation of compounds which are not otherwise suitable for transdermal delivery. The most promising approaches have been found to be iontophoresis, electroporation, sonophoresis, and chemical enhancement. Of these methods, chemical enhancement is the more established, and is currently commercially employed.
Chemical enhancers, or percutaneous penetration enhancers, have a broad spectrum of chemical structure depending on the application in which they are to be employed. The most common enhancers belong to the following groups: non-ionic surfactants, alcohols, fatty acid esters, and amines.
In order for enhancers to function properly, they must be present at the skin/device interface in sufficiently high quantity (generally 5-40% percent by weight based on the weight of the adhesive). As most transdermal drug delivery devices utilize pressure sensitive adhesives as a means of providing intimate contact between the drug delivery means and the skin, it is essential that the adhesive polymer be compatible with the specific enhancer used. In this way, adequate concentrations of the enhancer can be achieved by proper formulation with the adhesive without disrupting the physical integrity of the adhesive.
Polyacrylates are well suited to obtain the desired compatibility in that the polarity of the pendant moieties can be altered to accommodate the structure of the enhancer. Unfortunately, it is generally observed that when enhancers are compounded with these adhesives, the compatibility may be too great, resulting in dramatic reduction in the cohesive strength of the adhesive system.
To reduce the loss of adhesive integrity, attempts have been made to cross-link the adhesive polymers. Although this does increase the cohesive strength, the adhesive often does not possess sufficient flow to allow for long term adhesion to skin.
Clearly, then, the proper balance of enhancer compatibility, cohesive strength, and polymer flow is required for properly designed adhesive/enhancer systems.
Polymeric compositions are known which are comprised of backbone polymers having grafted thereto pendant polymeric moieties. The type of backbone polymer and graft polymeric moiety employed varies depending upon the desired characteristics of the end product. See, for example, U.S. Pat. Nos. 3,786,116; 3,832,423; 3,842,146; 3,862,077; 3,879,494; 3,928,255; 3,989,768; 4,085,168; 4,551,388; 4,554,324; 4,656,213; 4,693,776; 4,732,808; 4,871,812; and 5,352,516. These patents disclose various types of such polymers which may or may not exhibit pressure sensitive adhesive properties.
Typical of the type of polymeric compositions disclosed in the above patents are compositions comprised of a backbone polymer such as an acrylic or methacrylic backbone polymer having attached thereto a graft polymer comprised of a polymerizable macromolecular monomer such as styrene or alpha-methylstyrene. See, for example, U.S. Pat. No. 4,554,324, and commonly-assigned U.S. Pat. No. 5,352,516, among others, in this regard.
The acrylic pressure sensitive adhesives such as described in U.S. Pat. No. 4,554,324 and U.S. Pat. No. 5,352,516 may be made from an acrylic ester and a polar acrylic monomer. The polar acrylic monomer can be one or a mixture of acrylic acid, acrylamide, acrylonitrile, itaconic acid, etc. The acrylic ester can be any aliphatic ester of acrylic acid. Such monomers are typically polymerized free radically by solution, suspension or emulsion polymerization. The acrylate portion of the copolymer is generally present in a generally high concentration and renders the polymer tacky. The polar monomer increases the ability of the adhesive to bond to a surface.
U.S. Pat. Nos. 4,693,776 and 4,732,808 also disclose a pressure sensitive skin adhesive composition comprised of a macromer-reinforced acrylate copolymer. U.S. Pat. No. 4,871,812 discloses a moldable medical adhesive comprising a blend of an acrylate terpolymer adhesive containing a hydrophilic macromer moiety, and a reinforcing material which is a carbonylamido group containing polymer. U.S. Pat. No. 4,656,213 is directed to an acrylic hot melt pressure sensitive adhesive comprising a polyacrylate graft copolymer which may be plasticized to enhance the adhesive properties thereof.
Such adhesives have been found to suffer from the disadvantage that their adhesive properties are not sufficiently compatible with the skin (due to inadequate long-term tack) with the result that adhesive failure may occur after a short time due to movement of the skin.
It has accordingly been that reinforcement of the adhesive through the use of graft polymeric moieties or macromers, followed by plasticization with conventional percutaneous penetration enhancers, allows for the desired level of cohesiveness while allowing for a degree of adhesive flow which is essential for long term adhesion to skin.